Journal of Medicinal Chemistry
October 19, 2000
Joseph B. Blair, Deborah Kurrasch‐orbaugh, Danuta Marona‐lewicka et al.
132 citations
Fluorination of hallucinogenic tryptamines generally preserves their affinity and intrinsic activity at 5-HT2A/2C serotonin receptors but reduces affinity at the 5-HT1A receptor, except for one compound. 4-Fluoro-5-methoxy-DMT (compound 6) showed markedly enhanced 5-HT1A receptor affinity (Ki = 0.23 nM) and functional potency, greater than the standard 5-HT1A agonist 8-OH-DPAT, with an ED50 of 0.17 µmol/kg in a drug discrimination assay. Hallucinogen-like activity was attenuated or abolished for all fluorinated analogues. The findings suggest that while 5-HT2A activation is key for hallucinogenic effects, the 5-HT1A receptor may also play a role with tryptamines.
Journal of Medicinal Chemistry
September 1, 2002
David E. Nichols, Stewart Frescas, Danuta Marona‐lewicka et al.
89 citations
Lysergic acid amides containing a rigid dimethylazetidine ring—a constrained version of diethylamine—were synthesized and tested for hallucinogenic activity. The (S,S)-(+)-2,4-dimethylazetidine lysergamide showed slightly greater LSD-like behavioral effects in rats than LSD itself and had the highest affinity and functional potency at the serotonin 5-HT(2A) receptor, the presumed target for hallucinogens. Its receptor profile across a panel of screens most closely matched that of LSD. In contrast, the cis- and (R,R)-trans-dimethylazetidine lysergamides were less potent. These results suggest that the N,N-diethyl groups of LSD bind optimally in a conformation different from that seen in the solid state. Incorporating isomeric dialkylazetidines into other molecules may help model active conformations of dialkylamines and dialkylamides.
Journal of Medicinal Chemistry
September 1, 1997
Aaron Monte, Steve R. Waldman, Danuta Marona‐lewicka et al.
89 citations
Conformationally restricted bioisosteres of mescaline's methoxy groups—dihydrobenzofuran (8) and tetrahydrobenzodifuran (9)—were synthesized and tested against mescaline (1) in drug discrimination assays in rats trained to discriminate LSD from saline. Neither 8 nor 9 substituted for LSD: only 50% of rats given 8 and 29% given 9 selected the drug lever, whereas mescaline fully substituted (ED50 = 33.5 mumol/kg). All compounds showed micromolar affinity for 5-HT1A and 5-HT2A receptors in rat brain homogenate, but rank order of affinities at 5-HT2A sites reversed their behavioral potency. At 5-HT2A receptors, 8 and 9 were less efficacious (61% and 45% of maximal response), while all compounds matched serotonin's efficacy at 5-HT2C receptors.
Journal of Medicinal Chemistry
March 1, 1995
Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al.
25 citations
Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.
Journal of Medicinal Chemistry
June 21, 2006
Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al.
24 citations
A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.
Journal of Medicinal Chemistry
September 16, 1999
Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh et al.
15 citations
The R enantiomers of two rigid tryptamine analogues show a 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers, with no distinction based on the position of the oxygen group. The R enantiomers of both compounds have nearly identical affinities at the agonist-labeled receptor, while racemic versions of related compounds have about one-tenth the affinity. In rats trained to discriminate LSD or DOI from saline, the R enantiomers are about equipotent to DOI but about 10-fold less potent than LSD. One compound produced only partial substitution even at a dose nearly 5-fold higher than for the active R enantiomer. The results suggest these compounds would possess LSD-like psychopharmacology in humans.